This renewal application for the Cooperative Human Linkage Center (CHLC) represents a shift from our initial emphasis on polymorphic marker development, genotyping and genetic linkage map construction to a new emphasis on the study of genetic variation as it relates to the application of genome project tools and sequence alignments. As the primary genetic map goals have been achieved, it is now essential to move into the application of new classes of genetic variation that can be identified at far greater density than was previously imagined, and to understand how this variation can be used to improve our ability to characterize human genetic disorders and to finish construction of the high resolution physical (sequence) map. This program will consist of three projects. In the first, Dr. Murray will complete the initial analytic component of tandem repeat marker development and now expand into the identification of single nucleotide polymorphisms (SNP). This will be done in direct collaboration with Dr. Buetow's identification of these polymorphisms through a variety of database searching tools. The analysis of these SNP's will be carried out on representative populations to catalog the extent of their variation across different human population groups. High density studies of the behavior of genetic polymorphisms in a linkage disequilibrium setting will be explored across large physical contigs at a density 100 times greater than previously possible. Direct exploration of variant identification and its effect on structure/function relationships will also be incorporated through a developmental project. All analysis will be done in conjunction with the development of new genotyping strategies as a way of providing a resource for the next generation of human genetic mapping tools. In the second project, Dr. Buetow will explore the development of new analytic strategies for studying and applying genetic variation to human disorders and populations. He will expand his current informatics program that provides access to polymorphism and sequence data as well as access to a variety of linkage and sequence analytic tools. Direct supervision of the CEPH data as a primary resource for the study of human genetic variation will be incorporated and all of these tools and applications maintained through a user-friendly public interface. In the third project headed by Dr. Robert Weir, we will continue the development of our understanding of Institutional Review Boards (IRB) and the way in which they interface with human genetics and the ethical, legal and social issues raised by the Human Genome Project. An educational component of the project will include our continued development of resource materials for secondary school educators and the development of a project devoted to assisting high school students and better understanding the issues of informed consent and research activities as they relate to human genetics. This ELSl project explores the ethical and social implications of the genetic variation studied in Projects l and 2. The final product will be a new understanding of human genetic variation at the population, sequence and social level.